2IEH

Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer

Summary for 2IEH

• Entry DOI: 10.2210/pdb2ieh/pdb
• Descriptor: Kinesin-like protein KIF11, MAGNESIUM ION, POTASSIUM ION, ... (8 entities in total)
• Functional Keywords: beta-sheet core, flanked by three alpha-helices on each side, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 2
• Total formula weight: 83697.41

Authors

Garcia-Saez, I.,Kozielski, F. (deposition date: 2006-09-19, release date: 2007-01-23, Last modification date: 2023-08-30)

Primary citation

Garcia-Saez, I.,DeBonis, S.,Lopez, R.,Trucco, F.,Rousseau, B.,Thuery, P.,Kozielski, F.
Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.
J.Biol.Chem., 282:9740-9747, 2007

PubMed Abstract: Drugs that target mitotic spindle proteins have been proven useful for tackling tumor growth. Eg5, a kinesin-5 family member, represents a potential target, since its inhibition leads to prolonged mitotic arrest through the activation of the mitotic checkpoint and apoptotic cell death. Monastrol, a specific dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the biologically active compound in vitro and in cell-based assays. Here, we solved the crystal structure (2.7A) of the complex between human Eg5 and a new keto derivative of monastrol (named mon-97), a potent antimitotic inhibitor. Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer. The absolute configuration of this more active (R)-enantiomer has been unambiguously determined via chemical correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays) and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However, the difference was large enough for the protein to select the (R)- over the (S)-enantiomer. Taken together, these results show that in this new monastrol family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This considerably broadens the alternatives for rational drug design.

PubMed: 17251189
DOI: 10.1074/jbc.M608883200

Experimental method

X-RAY DIFFRACTION (2.7 Å)